Description

Ospemifene is a next-generation SERM (selective estrogen receptor modulator) that selectively binds to estrogen receptors and either stimulates or blocks estrogen’s activity in different tissue types. It has an agonistic effect on the endometrium.

Ospemifene is primarily metabolized by CYP3A4 and CYP2C9. CYP2C19 and other pathways contribute to the metabolism of Ospemifene. Estrogens and Estrogen Agonist/Antagonist: Do not use Ospemifene concomitantly with estrogens and estrogen agonists/antagonists. The safety of concomitant use of Ospemifene with estrogens and estrogen agonists/antagonists has not been studied. Fluconazole: Fluconazole, a moderate CYP3A / strong CYP2C9 / moderate CYP2C19 inhibitor, should not be used with Ospemifene. Fluconazole increases the systemic exposure of Ospemifene by 2.7-fold. Administration of fluconazole with Ospemifene may increase the risk of Ospemifene-related adverse reactions. Rifampin: Rifampin, a strong CYP3A4 / moderate CYP2C9 / moderate CYP2C19 inducer, decreases the systemic exposure of Ospemifene by 58%. Therefore, co-administration of Ospemifene with drugs such as rifampin which induce CYP3A4, CYP2C9 and/or CYP2C19 activity would be expected to decrease the systemic exposure of Ospemifene, which may decrease the clinical effect Ketoconazole: Ketoconazole, a strong CYP3A4 inhibitor, increases the systemic exposure of Ospemifene by 1.4-fold. Administration of ketoconazole chronically with Ospemifene may increase the risk of Ospemifene related adverse reactions. Warfarin: Repeated administration of Ospemifene had no effect on the pharmacokinetics of a single 10 mg dose of warfarin. No study was conducted with multiple doses of warfarin. The effect of Ospemifene on clotting time such as the International Normalized Ratio (INR) or prothrombin time (PT) was not studied. Highly Protein-Bound Drugs: Ospemifene is more than 99% bound to serum proteins and might affect the protein binding of other drugs. Use of Ospemifene with other drug products that are highly protein-bound may lead to increased exposure of either that drug or Ospemifene. Multiple Enzyme Inhibition: Co-administration of Ospemifenewith a drug known to inhibit CYP3A4 and CYP2C9 isoenzymes may increase the risk of Ospemifene -related adverse reactions.

Undiagnosed abnormal genital bleeding. Known or suspected estrogen-dependent neoplasia. Active DVT, pulmonary embolism (PE), or a history of these conditions. Active arterial thromboembolic disease [for example, stroke and myocardial infarction, or a history of these conditions. Hypersensitivity (for example, angioedema, urticaria, rash, pruritus) or any ingredients. It is contraindicated in women who are or may become pregnant. It may cause fetal harm when administered to a pregnant woman. Ospemifene was embryo-fetal lethal with labor difficulties and increased pup deaths in rats at doses below clinical exposures, and embryo-fetal lethal in rabbits at 10 times the clinical exposure based on mg/m2. If this drug is used during pregnancy, or if a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to a fetus.

Cardiovascular Disorders Malignant Neoplasms Vascular Disorders: Hot flush Reproductive System and Breast Disorders: Vaginal discharge Musculoskeletal and Connective Tissue Disorders: Muscle spasms Skin and Subcutaneous Tissue Disorders: Hyperhidrosis

Use in Pregnancy: Ospemifene is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to a fetus.Based on animal data, it is likely to increase the risk of adverse outcomes during pregnancy and labor. Adverse findings at maternally toxic doses included embryo fetal lethality in rats and rabbits, and neonatal mortality and difficult labor in rats. The reproductive effects observed are consistent with and are considered to be related to estrogen receptor activity of Ospemifene. Use in Lactation: It is not known whether Ospemifene is excreted in human breast milk. There are no data on the effects of Ospemifene on the breastfed child or the effects on milk production. Do not breastfeed while taking Ospemifene. Ospemifene was excreted in rat milk.

Cardiovascular Disorders: Risk factors for cardiovascular disorders, arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Stroke: In the clinical trials for Ospemifene (duration of treatment up to 15 months), the incidence rates of thromboembolic and hemorrhagic stroke were 1.13 and 3.39 per thousand women years, respectively in Ospemifene 60 mg treatment group and 3.15 and 0 per thousand women years in placebo. Coronary Heart Disease: In the clinical trials, two cases of myocardial infarction (MI) occurred in women receiving 60 mg of Ospemifene. In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo. Venous Thromboembolism: In the Ospemifene clinical trials, two cases of DVT occurred in women receiving Ospemifene 60 mg. Should a VTE occur or be suspected, Ospemifene should be discontinued immediately. If feasible, Ospemifene should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Endometrial Cancer: Ospemifene is an estrogen agonist/antagonist with tissue selective effects. In the endometrium, Ospemifene has agonistic effects. In the Ospemifene clinical trials (60 mg treatment group), no cases of endometrial cancer were seen with exposure up to 52 weeks. There was a single case of simple hyperplasia without atypia. Endometrial thickening equal to 5 mm or greater was seen in the Ospemifene up to 52 weeks treatment groups at a rate of 101.4 per thousand women vs. 20.9 per thousand women for placebo. The incidence of any type of proliferative (weakly plus active plus disordered) endometrium was 26.3 per thousand women in the Ospemifene up to 52 weeks treatment groups vs. 0 per thousand women for placebo. Uterine polyps occurred at an incidence of 19.6 per thousand women in the Ospemifene up to 52 weeks treatment groups vs. 8.3 per thousand women for placebo. Clinical surveillance of all women using Ospemifene is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Breast Cancer: Ospemifene 60 mg has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer. Severe Hepatic Impairment: Ospemifene should not be used in women with severe hepatic impairment Hypersensitivity Reactions: Inform postmenopausal women who have had hypersensitivity reactions to Ospemifene such as angioedema, urticaria, rash, and pruritus, that they should not take. Vaginal Bleeding: Inform postmenopausal women of the importance of reporting unusual vaginal bleeding to their healthcare providers as soon as possible. Hot Flashes or Flushes: Ospemifene may initiate or increase the occurrence of hot flashes in some women. Carcinogenesis: In a 2-year carcinogenicity study in female mice, ospemifene was orally administered at 100, 400, or 1500 mg/kg/day. No evaluation for carcinogenicity was conducted in male mice. There was significant increase in adrenal subcapsular cell adenomas at 4 and 5 times the human exposure based on AUC, and adrenal cortical tumors at 5 times the human exposure. In the ovary, an increase in sex cord/stromal tumors, tubulostromal tumors, granulosa cell tumors, and luteomas were also seen. These findings occurred at doses 2 to 5 times the human exposure based on AUC and are probably related to estrogenic/antiestrogenic effect of ospemifene in mice. Mutagenesis: Ospemifene was not genotoxic in vitro in the Ames test in strains of Salmonella typhimurium or at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells in the absence and in the presence of a metabolic activator system. In in vivo testing, ospemifene was not genotoxic in a standard mouse bone marrow micronucleus test or in a determination of DNA adducts in the liver of rats. Impairment of Fertility: The effect of ospemifene on fertility was not directly evaluated. In female rats and monkeys, decreases in ovarian and uterine weights, decreased corpora lutea number, increased ovarian cysts, uterine atrophy, and disrupted cycles were observed when given repeated daily oral doses. In male rats, atrophy of the prostate and seminal vesicles was noted. The effects on reproductive organs observed in animals are consistent with the estrogen receptor activity of ospemifene and potential for impairment of fertility.

Pediatric Use: Ospemifene is not indicated in children. Clinical studies have not been conducted in the pediatric population. Geriatric Use: Of the 2209 Ospemifene-treated women enrolled in the ten phase 2/3 trials of Ospemifene, >19 percent were 65 years of age or older. No clinically meaningful differences in safety or effectiveness were observed between these women and younger women less than 65 years of age. Renal Impairment: The pharmacokinetics of ospemifene in women with severe renal impairment (CrCL <30 mL/min) was similar to those in women with normal renal function. No dose adjustment of Ospemifene is required in women with renal impairment. Hepatic Impairment: The pharmacokinetics of ospemifene has not been studied in women with severe hepatic impairment (Child-Pugh Class C); therefore, do not use Ospemifene in women with severe hepatic impairment